<b>miR-432 Exacerbates Obesity-induced Dysregulation of Glucose and Lipid Homeostasis</b>

<p dir="ltr">MicroRNAs are key regulators of metabolic homeostasis, yet their role in obesity-associated dysfunction remains incompletely understood. Here, we identify miR-432 as a driver of systemic metabolic dysregulation. Serum microRNAs profiling revealed a positive correlation between miR-432 expression and obesity/type 2 diabetes mellitus. Functionally, adipose-specific miR-432 exacerbated HFD-induced obesity and insulin resistance. Similarly, hepatic-specific miR-432 aggravated hepatic steatosis and systemic glucose dysregulation, while skeletal muscle-specific miR-432 disrupted glucose homeostasis without affecting body composition. Mechanistically, miR-432 disrupted insulin sensitivity by inhibiting the PIK3R3/AKT pathway and perturbed lipid homeostasis by suppressing the PIK3R3/PPARα axis. Notably, obesity-induced miR-432 upregulation was predominantly localized in adipocytes and driven by the CDK5-PPARγ axis. Furthermore, adipocyte-derived exosomal miR-432 was identified as a mediator of systemic metabolic dysfunction, facilitating inter-tissue crosstalk in obesity. Collectively, our data demonstrate that miR-432 exacerbates obesity-induced dysregulation of glucose and lipid metabolism.</p>